Chronic kidney disease (CKD) patients receiving hemodialysis treatment (CKD stage 5) suffer from a variety of co-morbid diseases that may be mechanistically related. Protein malnutrition, muscle catabolism and wasting are especially common, and these lead to reduced muscle strength, declines in physical function, and low levels of physical activity. Physical inactivity exacerbates these functional declines, and also promotes cardiovascular disease (CVD) and bone disorders. This cycle of disease and disability greatly reduces the quality of life (QOL) and increases mortality rates in dialysis patients. Intradialytic protein supplementation and endurance exercise training are relatively low-cost therapies that have the potential to reduce the prevalence or severity of these co-morbid conditions, but few studies have directly assessed their efficacy. The objective of the proposed research is to evaluate the effects of intradialytic oral protein supplementation, with and without concomitant intradialytic exercise training (cycling), on measures related to physical function, QOL, CVD, and bone health. To address these questions, hemodialysis patients will be randomized to the following groups for 12 months: 1) usual care/control (CON); 2) intradialytic protein supplementation (PRO); or 3) intradialytic protein supplementation + exercise training (PRO+EX). Physical function, muscle strength, and QOL will be assessed by a variety of objective and subjective tasks, DXA will be used to measure lean mass, bone density, and abdominal aortic calcification, vascular ultrasound will be used to measure arterial stiffness and carotid intima-media thickness, and echocardiography will be used to assess cardiac structure and function. In addition, circulating levels of inflammatory mediators, mineral regulatory proteins, and growth factors that impact CVD risk and muscle and bone anabolism will be measured by standard biochemical assays to assess potential mechanisms by which protein supplementation and exercise training may influence these co-morbid conditions. We hypothesize that beneficial changes in physical function, functional CVD outcomes and risk factors, bone density, and QOL indices will occur in PRO+EX and PRO, but not in CON. Furthermore, the magnitude of these changes will be greatest in PRO+EX for all variables except those related to bone density. PUBLIC HEALTH RELEVANCE: This study will provide novel information regarding the effects of oral protein supplementation and exercise training on clinical outcomes and the QOL in dialysis patients. Results from this study will enable nephrologists to make more informed decisions regarding the extent to which these low-cost treatment strategies should be included as a component of the standard care in their clinics. Ultimately, this could lead to greater use of these treatment strategies and result in significant improvements in the health and QOL of this critically ill patient population.